Any hypothesis of schizophrenia etiology should ultimately consider its genetic diatheses, neurodevelopmental antecedents (i.e. fetal hypoxia), and environmental components. Schizophrenia is a heterogeneous disease, and hence there are advantages to studying patients with related disorders (e.g. schizotypal personality disorder), or subtypes of the disorder. DiGeorge syndrome is a genetic disorder characterized by delimited microdeletions in chromosome 22q11.2 and a high rate of schizophrenia. Because one copy of the 22q11 deleted region remains in DiGeorge syndrome, we hypothesize that some cellular and molecular pathways that utilize proteins encoded by 22q11.2 will be disrupted while others may remain relatively intact. The goal of this application is to use peripherally-accessible tissue from patients with this genetically- defined risk for schizophrenia in order to elucidate molecular pathways that have general applicability to other schizophrenia spectrum disorders. In Aim 1 we plan to profile the expression of 36 definitive genes in the known deleted region of DiGeorge syndrome (adolescent) patients and a control group without this deletion or mental illness. By studying populations at the premorbid stage, some of the confounding variables that attend chronic schizophrenia can be overcome. Furthermore, we plan to determine whether the genes (and/or proteins) that we find to have abnormal expression patterns in the DiGeorge syndrome patients are also affected in schizophrenic patients who do not have 22q11 deletions. Gene expression data in DiGeorge syndrome patients and idiopathic schizophrenia patients will be correlated with psychometric assessment scores. In Aim 2 we will examine the impact of hypoxia on these pathways using fibroblasts from DiGeorge syndrome patients and controls. Molecular pathways will be discerned in relation to other putative schizophrenia susceptibility genes with the aid of bioinformatics software that identifies pathways and inter-relationships at the level of genes, proteins, cells, and tissues. We anticipate these studies will open new opportunities for peripheral biomarkers that can elucidate schizophrenia pathogenesis, and may also reveal therapeutic targets that were never previously considered. PUBLIC HEALTH RELEVANCE;Despite progress on many fronts, the causes of schizophrenia are not known. If researchers can discover the underlying cellular defects in schizophrenia, novel and improved treatments can be designed. This study examines such cellular abnormalities in schizophrenia and a "variant" of the disease called DiGeorge syndrome.